A. Field of the Invention
This invention relates to compounds, pharmaceutical compositions and methods for the treatment of myosin heavy chain (MyHC)-mediated diseases, and in particular, heart failure.
B. Related Art
Heart failure is a pathophysiological state in which the heart fails to pump blood at a rate commensurate with the requirements of the metabolizing tissues of the body. It is caused in most cases—about 95% of the time—by myocardial failure.
The contractile proteins of the heart lie within the muscle cells, called myocytes, which constitute about 75% of the total volume of the myocardium. The two major contractile proteins are the thin actin filament and the thick myosin filament. Each myosin filament contains two heavy chains and four light chains. The bodies of the heavy chains are intertwined, and each heavy chain ends in a head. Each lobe of the bi-lobed myosin head has an ATP-binding pocket, which has in close proximity the myosin ATPase activity that breaks down ATP to its products.
The velocity of cardiac muscle contraction is controlled by the degree of ATPase activity in the head regions of the myosin molecules. The major determinant of myosin ATPase activity and, therefore, of the speed of muscle contraction, is the relative amount of the two myosin heavy chain isomers, α and β (MyHC). The α-MyHC isoform has approximately 2-3 times more enzymatic activity than the β-MyHC isoform and, consequently, the velocity of cardiac muscle shortening is related to the relative percentages of each isoform. For example, adult rodent ventricular myocardium has approximately 80-90% α-MyHC, and only 10-20% β-MyHC, which explains why its myosin ATPase activity is 3-4 times greater than bovine ventricular myocardium, which contains 80-90% β-MyHC.
When ventricular myocardial hypertrophy or heart failure is created in rodent models, a change occurs in the expression of MyHC isoforms, with α-MyHC decreasing and β-MyHC increasing. These “isoform switches” reduce the contractility of the hypertrophied rodent ventricle, ultimately leading to myocardial failure. This pattern of altered MyHC gene expression has been referred to as reversion to a “fetal” expression pattern because, during fetal and early neonatal development, β-MyHC also dominates in rodent ventricular myocardium.
It has been shown that myocardial function declines with age in animals. Cellular and molecular mechanisms that account for age-associated changes in myocardial performance have been studied largely in rodents. Among other changes, marked shifts in MyHC occur in rodents, i.e., the β isoform becomes predominant in senescent rats. Steady-state mRNA levels for α-MyHC and β-MyHC parallel the age-associated change in the MyHC proteins. The myosin ATPase activity declines with the decline in α-MyHC content, and the altered cellular profile results in a contraction that exhibits a reduced velocity and a prolonged time course.
Human atrial myocardium may undergo similar isoform switches with hypertrophy or failure, although human ventricular myocardium, the basis for the majority of cases of heart failure (greater than 90% of cases), has not been consistently shown to exhibit this pattern. Several studies have examined this issue in autopsy cases, but did not find biologically significant expression of the α-MyHC isoform in putatively normal hearts. Since there was thought to be no significant expression of α-MyHC in normal hearts, a down-regulation in α-MyHC was not thought to be a possible basis for myocardial failure in humans. There was one early report that the amount of α-MyHC, although extremely small to begin with, was reduced in failing human myocardium. (Bouvagnet, 1989). However, more recent reports have shown the existence of appreciable levels of a-MyHC in the human heart at both the mRNA and protein level. At the mRNA level, 23-34% of the total ventricular mRNA is derived from α-MyHC (Lowes et al., 1997; Nakao et al., 1997), while approximately 1-10% of the total myosin protein content is α-MyHC (Miyata et al., 2000; Reiser et al., 2001). These changes in MyHC isoform content are sufficent to explain the decrease in myosin or myofibrillar ATPase activity in the failing human heart (Hajjar et al., 1992; Pagani et al., 1988).
Data generated in the 1990's suggested that β myosin heavy chain mutations may account for approximately 30-40% percent of cases of familial hypertrophic cardiomyopathy (Watkins et al., 1992; Schwartz et al., 1995; Marian and Roberts, 1995; Thierfelder et al., 1994; Watkins et al., 1995). A patient with no family history of hypertrophic cardiomyopathy presented with late-onset cardiac hypertrophy of unkonwn etiology, and was shown to have a mutation in α-MyHC (Niimura et al., 2002). Two important studies have shown even more convincingly the important role of the MyHC isoforms in cardiovascular disease. Lowes et al. (2002) showed that using beta blockers to treat dilated cardiomyopathy led to increased levels of α-MyHC and decreased levels of β-MyHC that directly corresponded to improvement in disease state. In fact, the changes in α-MyHC noted in those studies was the only factor shown to correlate with improvement in cardiac function. Equally convincingly, Abraham et al. (2002) have shown that myosin heavy chain isoform changes directly contribute to disease progression in dilated cardiomyopathy. These studies show the importance and need for an agent that can alter, if not reverse, the isoform switching that occurs in the MyHC isoforms in cardiovascular disease.